Field of Invention
The invention relates to antiviral compounds and methods of their preparation.
Related Art
Acyclic nucleoside phosphonates (ANPs) are broad spectrum antiviral agents that are highly potent against orthopox viruses, including cowpox, vaccinia, and variola (smallpox) virus [1]. The prototype member of the ANPs is (S)-9-(3hydroxy-2-phosphonyl-methoxypropyl)adenine ((S)-HPMPA, 1, see FIG. 1), first described 1986 for its activity against DNA viruses [2]. Its cytosine analogue, (S)-HPMPC (cidofovir, 2, see FIG. 1) [3] has been shown to have similar therapeutic potential against virtually all DNA viruses as well as other adeno-, papiloma-, polyoma-, and poxvirus infections. Cidofovir is used in the clinic for the treatment of AIDS patients infected with cytomegalovirus (CMV).
(S)-HPMPC is effective in vitro and in animal model infections but has low oral bioavailability, and must be delivered intravenously [4]. This condition limits the therapeutic scope of this and other ANP drugs. Moreover, after intravenous injection drugs of this class tend to accumulate in the kidney leading to renal toxicity [5,6]. Thus, there is a need for more effective, orally bioavailable forms of these drugs.
Several prodrug approaches to improve oral absorption of antiviral nucleoside analogues by incorporating various phosphonate anion masking groups have been developed [7].